ABSTRACT Pulmonary disease remains a leading cause of morbidity and mortality in HIV infection despite the availability of combination anti-retroviral therapy (ART). Chronic obstructive pulmonary disease (COPD) is of particular interest in the current era of HIV infection because it is accelerated in those with HIV and is likely to increase as this population lives longer with chronic HIV. Pathogenesis of HIV-related COPD is not completely understood, but it is hypothesized that accelerated disease could result from co-infections that may up-regulate pulmonary HIV replication or amplify pulmonary inflammatory responses leading to tissue damage. We have accumulated evidence in both humans and animal models that Pneumocystis (Pc) is an important pathogen in the development of COPD in both the HIV+ and HIV- populations. In HIV+ subjects, Pc colonization is frequent even among those receiving anti-Pc prophylaxis and among those with high CD4 cell counts who are receiving antiretroviral therapy. Pc colonization in HIV+ subjects is associated with worse airway obstruction and anatomic emphysema. In a primate model of HIV infection, we have shown that Pc colonization correlates with airway obstruction and emphysema. Little is known regarding host susceptibility to Pc colonization in the context of HIV immunosuppression. In human studies and in a primate model of HIV/Pc co-infection, our group has shown that antibody response to the Pc protein, KEX1 correlates with protection from colonization and obstructive lung disease. Low KEX1 antibody titers in HIV+ humans also predict subsequent risk of Pc pneumonia (PcP), independent of CD4+ T cell count, and low KEX1 titers in HIV-negative smokers are associated with COPD. These findings support the hypothesis that immunity to KEX1 may be critical to controlling Pc colonization and preventing or slowing development of obstructive lung disease. The objectives of this proposal are to 1) define immune correlates of protection against natural Pc colonization in a macaque model of HIV and Pc co-infection;2) to examine the development of a protective B cell response to KEX1, and 3) to develop and test the hypothesis that prophylactic and therapeutic vaccination strategies that target CD4 T cell-independent mechanisms of enhancement of Pc-specific humoral immunity will prevent or control Pc colonization and COPD in a highly relevant model of HIV infection. PUBLIC HEALTH RELEVANCE: Infection of immunocompromised patients with the fungal pathogen, Pneumocystis remains a serious cause of pulmonary disease. These studies will identify effective immune responses to Pc and will test vaccine strategies to prevent or treat Pneumocystis infection and its pulmonary complications in a highly relevant pre-clinical model of HIV infection.